Grant Abstract: The VITamin D and OmegA-3 TriaL (VITAL): Post-Intervention Follow-Up

Grant Number: 2R01AT011729-17A1
PI Name: Manson
Project Title: The VITamin D and OmegA-3 TriaL (VITAL): Post-Intervention Follow-Up

Abstract: This is a renewal application for a 5-yr extension of post-intervention follow-up of the VITamin D and OmegA-3 TriaL (VITAL). VITAL, which enrolled 25,871 US adults (including 5,106 Black and 1,013 Hispanic individuals), is the largest randomized controlled trial of vitamin D3 (vit D, 2000 IU/d) and marine omega-3 fatty acids (n-3 FAs, 1 g/d) supplementation for cancer and CVD prevention in the general population. Although no significant effect was found for the primary endpoints of total cancer or major CVD events during the trial period (5.3-yr), there were promising signals for vit D reducing cancer mortality and advanced cancer in the overall cohort, and reducing total cancer in adults with normal weight. Further, n-3 FAs reduced myocardial infarction and other coronary endpoints in the overall cohort, with large risk reductions in Black adults. Extended longitudinal follow- up is needed to address these promising signals, and to enable unprecedented evaluation of potential durable (persistent) and latent effects vit D and n-3 FAs to better inform precision nutritional guidelines. Our Aim 1 will extend the follow-up to 16 yrs (11 yrs post-intervention), to accrue additional cases, and to powerfully examine promising trial-phase signals and long-term effects of vit D and n-3 FA on cancer, CVD, and total mortality. Further, as a nationwide, longitudinal, and deeply-phenotyped cohort, VITAL is optimally positioned to address critical research gaps regarding social and environmental determinants of health. Specifically, longitudinal data on how psychosocial and environmental stressors at individual- and community-levels act independently and synergistically in relation to long-term health are limited; and specific biological pathways linking stressors to health are yet to be elucidated utilizing novel multi-omic approaches. Leveraging the rich data in VITAL (e.g., clinical, questionnaires, geospatial, imaging, metabolomics, and proteomics), our Aim 2 will systematically examine the associations of psychosocial and environmental stressors at individual- and community-levels with risk of CVD, cancer, and all-cause mortality over 16 yrs of follow-up, and evaluate association differences by race and sex. To provide mechanistic insight, our innovative Aim 3 will identify proteomic and metabolomic alterations by which adverse stressors are associated with cardiometabolic risk and aging biomarkers in the VITAL-Clinic sub-cohort. Building upon prior data supporting a role of nutritional/lifestyle factors in alleviating adverse effects of stress, our Aims 2 and 3 will further examine whether vit D and n-3 FAs (leveraging our trial design) and a healthy lifestyle mitigate risks related to adverse stressors, thus informing preventive strategies. Replication analyses for all Aims will be performed in DO-HEALTH, an interventional trial of similar design. VITAL collected a wealth of data, supported 28 ancillary studies, and has been extremely productive. This innovative and cost-efficient proposal will maintain its infrastructure, address long-term effects of vit D and n-3 FAs, and provide new evidence on psychosocial and environmental stressors at individual and community- levels in relation to long-term health to inform evidence-based prevention and policy making.

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